Since the late 1990's, scientists have unraveled several of the complex processes by which normal cells become cancer cells and developed a deeper knowledge of the heterogeneous nature of tumors. The mutational events which result in aberrant growth factor signaling in bulk tumor cells has led to the theory of “oncogene addiction”, that ascribes cancer cell proliferation and survival to a dependence upon the activation of certain pathways or on the activity of oncogenic proteins within these pathways. More recently, researchers have found small populations of tumor cells with “stem cell” like characteristics, commonly referred to as cancer stem cells, within human primary tumor samples. These newly described cancer stem cells replicate more slowly, are more resistant to conventional chemotherapy, and their survival appears to be a major contributor to tumor re-growth following surgery and/or chemotherapy. In contrast to bulk tumor cells, cancer stem cells appear to be more reliant on embryonic pathways for their proliferation and survival traits.
The Hedgehog (Hh) Pathway: Several key signaling pathways (e.g. Hedgehog, Notch, Wnt) are involved in most processes essential to the normal development of an embryo. The Hedgehog pathway was initially discovered in Drosophila by Dr. Eric Wieschaus and Dr. Christiane Nusslein-Volhard, and is a major regulator for cell differentiation, tissue polarity and cell proliferation. The Hedgehog pathway plays a crucial role in tumorigenesis when reactivated in adult tissues through either mutation or other mechanisms. The Hedgehog pathway is an important driver of tumorigenesis in at least one-third of all types of cancer.
Oncogenic mutations in the Hedgehog pathway have been found in basal cell carcinoma and medulloblastoma, and Hh over expression is associated with at least pancreatic, colon, gastric, liver and prostate cancer. The estimated incidence of cancers with ligand dependent activation of Hh in the US is >200,000 cases annually and approximately 10-fold higher worldwide.
Hh Pathway Over Expression in Solid Tumors2008 NewHh PathwayUS CasesExpressionTumor(Deaths)(% Total)ReferencesColon108,07092,940Douard et al, Surgery 136,(49,960)(86%)665-670 (2006)Lung215,02053,755Watkins et al, Nature 422,(161,840)(25%-50%)313-317 (2003)Pancreas37,68018,840Thayer et al, Nature 425,(34,290)(50%)851-855. (2003)Gastric21,50013,760Ma et al, Carcinogenesis(10,880)(64%)26, 1698-1705 (2005)Hepatocellular21,37010,685Huang et al Carcinogenesis(18,410)(50%)27, 1334-1340 (2006)Prostate186,32055,896Sanchez et al, PNAS 101,(28,660)(30%)12561-12566 (2004)Total589,960245,876(41%)
More is becoming known about the role of cancer stem cells in the recurrence and spread of cancer. Control of the self-renewal and differentiation processes in cancer stems cells is thought to be regulated by embryonic pathways including Hedgehog. Growing evidence suggests that these pathways are deregulated in several cases, leading to abnormal cellular expansion and the formation of cancer.
Human Sonic Hedgehog protein (SHh) is synthesized as a 45 kDa precursor protein that undergoes autocleavage to yield a 20 kDa fragment that is responsible for normal Hedgehog pathway signaling. At the cell surface that Hedgehog signal is thought to be relayed through the 12 transmembrane domain protein, Patched (Ptc) and the 7 transmembrane domain protein, Smoothened (Smo). In normal adult cells, Ptc serves as a negative regulatory of Smo activity. The binding of SHh to Ptc inhibits the normal inhibitory effect of Ptc on Smo allowing Smo to transduce the SHh signal across the plasma membrane. The signal cascade initiated by Smo results in the activation of Gli transcription factors that migrate to the nucleus where they control target transcription factors effecting cell growth and differentiation in embryonic cells and where uncontrolled activation in adult cells is associated with malignancies.